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United States Patent 3,102,118 PROCESS FOR PRODUCING EMETINE AND ANALOGUES THEREOF Dennis Edward Clark, Chalfont St. Peter, and Alexander Crawford Ritchie, Harrow, England, and Thomas Walker, Worli, Bombay, India, assignors to Glaxo Group Limited, Greenford, Middlesex, England, a British company No Drawing. FiledMar. 16, 1962, Ser. No. 180,346 Claims priority, application Great Britain Mar. 17, 1961 8 Claims. (Cl. 260-488) This invention relates to the production of emetine and its analogues.

Our copending application No. 113,639, filed May 31, 1961, describes conversion of compounds having the skeletal structure (where R and R are hydrocarbon groups, for example alkyl groups such as methyl groups) into compounds having the skeletal structure the conversion of compounds of structure II into emetine or related compounds.

Compounds of Formula I exist in two steroisomeric forms which we have denoted IA and 1B. These differ in the configuration at the 1-position of the tetrahydroisoquinoline ring and may be represented structurally by the formulae \/N l t L) o o R NCH2CH2.COR

. benzophenone.

and

We have found that appropriately substituted compounds of structure 113 may be converted to emetine While similarly substituted compounds of structure IA are converted by the same series of reactions into iso-emetine. For convenience we have termed intermediates derived without inversion from compounds of-structure IA compounds of the A-series while intermediates derived without inversion from compounds of structure LB may be termed compounds of the B-series.

We have found that the -N -hydroxy-a1kyl group of compounds of skeletal stnucture II, may be removed by oxidation with an alkali metal alkoxide and a ketone stable in the presence of alkali, preferably with an alkali metal tertiary alkoxide, for example sodium or, preferably, potassium t-butoxide and a diaromatic ketone such as The oxidation conditions thus elfect not only oxidation but removal of the N-hydroxyalkyl side chain.

According to the present invention, therefore, we provide a process for the preparation of compounds of the skeletal formula where R is a hydrocarbon group, in which a compound of the skeletal formula v where R and R are hydrocarbon groups, is subjected to oxidation with an alkali metal alkoxide and a ketone stable in the presence of alkali.

The alkali metal butoxide is preferably an alkali metal tertiary alkoxide, such as sodium or, preferably potassium, t.butoxide. The 'ketone is preferably a di-aromatic ketone e.g. benzophenone.

In order to prepare the compounds of Formula II used as starting material, it is necessary to reduce the double bond and both carbonyl groups of the compound of skeletal Formula I. We have found that the reduction of the double bond may be effected with a metal/ ammonia or metal/amine reducing system and results in simultaneous reduction to a hydroxyl group of the saturated keto-group of the N-keto-alkyl side chain. The ketogroup of azp-unsaturated system is not reduced under these conditions and the product is a compound of the skeletal structure in which R and R have the above meanings, often in admixture with the isomeric compound of skeletal formula The reducing system is conveniently an alkali metal or alkaline earth metal/ ammonia system and while for example sodium, potassium or calcium are suitable, lithium is the preferred metal for this purpose. The metal may for example be added to the ammonia and the compound of Formula I added in solution in an inert solvent, e.g. an ether, such as diethyl ether or tetrahydro furan or a hydrocarbon solvent such as, benzene or toluene etc.

It is then necessary to reduce the 3 acyl groulp present in the compounds of structure IV and V. The 3-ethy1 group in l-emetine is equatorial as in compounds of structure V and it is necessary, therefore, that compounds of structure IV should be converted into compounds of structure V before reduction of the said keto group. Such con version may be effected under strong errolising conditions for example in the presence of concentrated aqueous acid for example aqueous mineral acid such as hydrochloric, sulphuric or phosphoric acid e.g. 5 N sulphuric acid or alkali e.g. an alkali metal hydroxide such as sodium or potassium hydroxide or strong organic base, e.g. triethylamine. This conversion may take place spontaneously in a subsequent reduction step if the reduction conditions are sufiiciently basic or acidic.

The reduction of the keto group in compounds of gen eral structure V may be achieved by a number of methods,

0 such as are present in emetine may be hydrolysed.

4 for example by reaction with hydrazine and alkali (Wolff- Kishner reduction).

The preferred method, however is to convert the keto group into a thioketal 'group, e.g. by reaction with ethanedithiol under acid conditions, for example in the presence of a mineral acid such as hydrochloric, sulphuric acid etc., and to treat the resulting thioketal with a Raney metal, such as Raney iron or cobalt or preferably, Raney nickel, advantageously in the presence of hydrogen or with hydrazine and alkali under Wolff-Kishner conditions.

Although in the above description of the novel process according to the invention, no distinction has been drawn between compounds of the A and of the B series, it will be understood that the reactions described apply to compounds of either series.

The compounds having the skeletal Formulae I to V which are concerned in the processes described above may be variously substituted, according to the substitution in the desired product. Thus, for example, substituents which may be present include alkyl, aralkyl, aryl, alkoxy, analk oxy, aryloxy, alkyl, aralkyl-, or aryl-thio groups. Swbstituents may also occupy more than one position as in methylene dioxy groups. Preferred groups in the aromatic rings are alkoxy and methylene dioxy groups; especially preferred are methoxy groups in the 9, 1'0, '6 and 7' positions the remaining positions being unsubstituted. Some of the groups referred to above may not withstand the conditions employed in the processes described above and, for example, methoxy groups in the aromatic rings It will be appreciated, therefore, that subsequent reaction steps may be required to reform substituents which have been converted. Thus, for example, where a methoxy group which has been hydrolysed is, in fact, required in the final product, re-methylation will be required, e.g. by reaction with diazomethane in the presence of methanol or, preferably, phenylthiomethylammonium chloride in a solvent such as xylene.

In order that the invention may be well understood we give the following examples by way of illustration only:

EXAMPLE 1 3 Acetyl-J,2,3,4,6,7-Hexahydr0-9,10-Dimeth0xy-2(1,2,3,

4 T etrahydro 2 (3'Hydr0xybutyl)6,7-Dimeth0xy-Is0- quin0l-1-Yl)Methyl -11b [H] -Benz0 [a] Quinolizine B SERIES (a) 3 acetyl-l,4,6,7-tetrahydro-9,10-dimethoxy-2(1,2, 3,4 tetrahydro-2 (3'-oxobutyl)-6,7-dimethoxyisoquinol-lyl)methyl -llb[H]-benzo [a]quin0lizine (B series) (10 g.) in anhydrous tetrahydrofuran (150 ml.) was added to a solution of lithium (1.2 g.) in liquid ammonia (500 ml.) and the mixture stirred [for 30 minutes at reflux temperature. The blue colour was discharged by the addition of acetone '(ca. 11 ml.) followed by amrnbnium chloride (10 g.). Evaporation, at first at atmospheric pressure to remove the ammonia, and then in vacuo to eliminate organic solvent, gave a pale foam. Water ml.) and chloroform (40 ml.) were added. The layers were separated and the aqueous phase extracted with chloroform (4X40 ml.). The first four extracts were combined and washed with water (3x100 rnl.), the washes being back-extracted with the fifth extract. Removal of the solvent in vacuo gave a pale foam.

The latter was heated at 100 C. with 5 Nasulphuric acid for 30 minutes to eifect equilibration. The solution was cooled, diluted with water containing crushed ice, benzene (100 ml.) added, and the mixture basified by the addition of potassium carbonate. Isolation of the reaction product in benzene solution (ca. 200 ml.) was accomplished by an extraction and Washing technique similar to that described in the preceding paragraph. Removal of the solvent gave a pale froth (9.56 g.) containing the desired product.

(b) Purification via the ethylene thioketal.The total crude product formed in (a) above was taken up in an anhydrous methanol 200 ml.) and the solution saturated at C. with anhydrous hydrogen chloride. Ethane dithiol (3 ml.) was added and the mixture allowed to stand for 2 hours. Removal Of the solvent by evaporation in vacuo gave a pale gum, which was taken up in water and basified With 2 N-sodium hydroxide. Extraction with benzene (4X50 ml.) and washing with 2 N-sodium hydroxide (2X50 ml.) and water (X50 ml.) was carried out as above. The crude ethylene thicket-a1 was obtained as a pink froth (8.6 g.) by evaporation or the solvent.

This material was placed on a column of alumina (grade H) (300 g.) in benzene and eluted successively with benzene (1.5 1.), 5% ethyl acetate-benzene (1 l.) ethyl acetate-benzene (2 1.), 20% ethyl acetate-benzene (6 1.), 30% ethyl acetate-benzene (1 l.) and 40% ethyl acetate-benzene (l 1.). The last three eluants gave rise to a total of 3.0 :g. of the desired thioketal, which paper chromatography showed to be substantially homogeneous.

The hydriodide of this material crystallised from etherethanol, M.-P. 207209 C. (d.). (Found: C, 44.13; H, N, S, I, C35H5005N2S2.2HI;3H20 requires C, 44.12; H, 6.14; N, 2.94; S, 6.73; I, 26.64%.)

T etra!zydr0-2-(3'-H ydroxybutyl 6,7-Dimeth0xy Isoquinol-1-Yl Methyl) -11 b [H] Benzo [a] Quinolizine A SERIES The reduction of the A isomer of 3-acetyl-1,4,6,7- tetrahydro-9,10-dimethoxy-2-(1,2,3,4 tetrahydro 2(3'- oxobutyl -6,7-dimethoxy-isoquinol- 1 -yl methyl) 1 1b[H] benzo [a]quinolizine (5 g.) in tetrahydro furan solution (150 ml.) was carried out with lithium (0.6 g.) in ammonia (300 ml.) exactly as described in the preceding example. The total crude froth (5.34 g.) was equilibrated with 5 N-sulphuricacid (50 ml.) and the crude ketone (4.38 g.) isolated as before.

Reaction with ethane-dithiol (4.3 ml.) in dry saturated methanolic hydrogen chloride (80 ml.) gave the ethylene thioketal (3.86 g.) as a red team by the previously described procedure.

This material was absorbed on a column of alumina (100 -g.: grade H) in benzene (and eluted successively with 10% ethyl acetate-benzene (300 mL), 25% ethyl acetate-benzene (400 ml.), 50% ethyl acetate-benzene (300 ml.), and ethyl acetate (1.4 1.). The last eluant gave rise to the desired thioketal (1.8 g.) which paper chromatography showed to be almost pure.

The hydrochloride separated from methanol as a white crystalline solid and was recrystallised from methanolet-her, M.P. 2l5-220 C. (d.). (Found: C, 53.42; H, 7.39; N, 3.52; S, 8.80; Cl, 9.33. C H O N S 2HCL4H O requires C, 53.34; H, 7.68; N, 3.56; S, 8.14; Cl, 900%.)

EXAMPLE 3 (j: )N- (3-Hydr0xybmyl) Emetine The ethylene thioketal vformed in (i) (b) (0.873 g.) in dry I.M. S. (50 ml.) was shaken under hydrogen (50 atmospheres pressure) with Raney nickel catalyst (W4: 7 ml. slurry) for 3 hours at 75-80 C. and then for a further 7 hours while the autoclave cooled to room temperature.

The catalyst was filtered off, washed with ethanol and the combined filtrate and washings evaporated in vacuo to a pale gum. Addition of ether and reevaporation yielded a white iroth (351 mg.) whose R value and IR. spectrum were similar to those of N-(3-hydroxybutyl) emetine made from the natural alkaloid.

The hydrochloride separated from ethanol on the addition of ether as a white amorphous solid MJP. ca. 212 C. (d.) with previous sintering. (Found C, 58.52; H, 8.24; N, 3.87; Cl, 10.04. C H O N 2HCL3H O requires C, 58.31; H, 8.31; N, 4.12; Cl, 10.43%.)

6 EXAMPLE 4 5 in dry I.M.S. (30 ml.) was shaken under hydrogen at atmospheric pressure and 50 C. with Raney nickel catalyst (W4; 5 ml. slurry) for 24 hours. The working-up procedure described in the preceding example gave rise to (i) N-(3-hydroxybutyl)isoemetine as a white loam (0.46 g).

The amorphous perchlorate separated from aqueous acidic solution, MJP. 165175 C. (resinous melt). (Found: C, 51.63; H, 6.79; N, 3.25; Cl, 9.01.

c ngom znclo n o requires C, 51.36; H, 6.79; N, 3.63; Cl, 9.19%.)

EXAMPLE 5 (i) Em eline To a solution of potassium (0.52 g.; 6 molar equivalents) in dry t-butanol (20 ml.) under nitrogen was added dry benzophenone (4.1 -g.; 10 molar equivalents) and a solution of (i) N-(3-hydroxybutyl) emetine (1.23 g.; 1 molar equivalent) in dry benzene (50 ml.). The solution was stirred at reflux under nitrogen for 24 hours, cooled, and acidified with ethanolic hydrogen chloride. After removal of the solvents by evaporation in vacuo, the residue was taken up in water (20 ml.) and extracted with benzene (3x25 ml.). The benzene extracts were washed with water (2X20 ml.) and the organic layer was discarded. The total combined aqueous layers were basified with 2 N-sodium hydroxide solution and extracted with benzene (3X30 ml.). The combined 'organic layers were washed with water (2x50 ml), dried (MgSO and evaporated in vacuo to yield i) emetine as a white foam (0.955 g). The R value and LR. spectrum of this material resembled those of the natural alkaloid.

The hydrobromide separated from methanol as a bulky amorphous solid ('M.P. 2268 C., resinous melt, finally decomposing at ca. 245 C.) having at least half the activity of (i) emetine hydrochloride against entarnocba histolytica in rats.

EXAMPLE 6 (i) Isoemetine By procedure similar to that described in the preceding example (:)N-3 (hydroxybutylfisoemetine (0.149 g.) was converted into (:L)isoemet-ine (0.108 :g.) identified by its R value.

This material gave a hydrochloride, M.P. 2579 C. (d.), after crystallisation from methanol-ether, identical in all respects with the (i) isoemetine hydrochloride obtained by hydrogenation of (i) O-methyl psychotrine hydrogen oxalate.

EXAMPLE 7 3-acetyl-1,4,6,7-tetrahydro-9,lO-dimethoxy-Z (1,2,3,4- tetrahydro-2(3'-oxobu=ty1)-6,7dimethoxy-isoquinol-l yl methyl)-11b[H]-benzo[a]quinolizine (B series) (5 'g.) was reduced as above with lithium in liquid ammonia. The crude product, isolated as before, was taken up in anhydrous methanol (50 m1.) and saturated with anhydrous hydrogen chloride without cooling. The heat of solution caused the mixture to boil. The solution was cooled to 0, ethane dithiol (3 ml.) added, and the crude ethylene thioketal obtained as before.

The crude foam (5.42 g.) in benzene was absorbed on a column of silica gel g.) and eluted successively With dry benzene (500 ml.), 50% ethyl acetate-benzene (850 ml), and ethyl acetate (1.5 1.).

The ethyl acetate traction gave the desired ethylene thioketal (2.83 g.), homogeneous on a paper chromatogram or silica chromatostrip.

We claim:

1. A process for the preparation of a compound of the formula in which a compound of the formula where R is alkyl of 1-3 carbon atoms, is subjected to oxidation with an alkali metal alkoxide in the presence of a ketone stable in the presence of alkali.

2. A process as claimed in claim 1 wherein said ketone is a diaromatic ketone.

3. A process as claimed in claim 2 wherein said diatomatic ketone is benzophenone.

4. A process as claimed in claim 1 wherein said alkali metal alkoxide is an alkali metal tertiary butoxide.

5. A process as claimed in claim 1 wherein said alkali metal alkoxide is potassium tertiary butoxide.

6. A process as claimed in claim 1 wherein said alkali metal alkoxide is potassium tertiary butoxide and said ketone is benzophenone,

7. A process as claimed in claim 6 wherein the reaction is effected at the reflux temperature of the reaction mixture.

8. A process as claimed in claim 1 wherein the final product is reacted with a methylating agent to remethylate such hydroxyl groups as have been formed during the process by hydrolysis of the methoxy groups of the starting compound.

No references cited. 

1. A PROCESS FOR THE PREPARATION OF A COMPOUND OF THE FORMULA 